Interactive Pathways of Key Prognostic Factors in Severe Asthma: A Bayesian Network Comparison of Clinical Trials & Real-World Data

Chandra Prakash Yadav¹, Laura Huey Mien Lim¹, David Price², Rupsa Roy³, Juang Yah Ru¹, Richard Beasley⁴, Christer Janson⁵, Mariko Siyue Koh⁶, Eileen Wang⁷, Michael E Wechsler⁸, David J Jackson⁹, John Busby¹⁰, Liam G Heaney¹¹, Paul E Pfeffer¹², Bassam Mahboub¹³, Diahn-Warng Perng Steve¹⁴, Borja G Cosio¹⁵, Luis Perez-de-Llano¹⁶, Riyad Al-Lehebi¹⁷, Désirée Larenas-Linnemann¹⁸, Mona Al-Ahmad¹⁹, Chin Kook Rhee²⁰, Takashi Iwanaga²¹, Enrico Heffler²², Giorgio Walter Canonica²³, Richard Costello²⁴, Nikolaos G Papadopoulos²⁵, Andriana I Papaioannou²⁶, Celeste M Porsbjerg²⁷, Carlos A Torres-Duque²⁸, George C Christoff²⁹, Todor A Popov³⁰, Mark Hew³¹, Matthew Peters³², Peter G Gibson³³, Jorge Maspero³⁴, Celine Bergeron³⁵, Saraid Cerda³⁶, Elvia Angelica Contreras³⁷, Wenjia Chen³⁸

Affiliations

¹ Saw Swee Hock School of Public Health, National University of Singapore.
² Optimum Patient Care Global, Cambridge, UK; Observational and Pragmatic Research Institute, Singapore, Singapore; Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.
³ Centre for Quantitative Medicine, Duke NUS Medical School, Singapore.
⁴ Medical Research Institute of New Zealand, Wellington, New Zealand.
⁵ Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
⁶ Duke-NUS Medical School, Singapore; Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore.
⁷ Division of Allergy & Clinical Immunology, Department of Medicine, National Jewish Health, Denver, CO, USA; Division of Allergy & Clinical Immunology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
⁸ NJH Cohen Family Asthma Institute, Department of Medicine, National Jewish Health, Denver, CO, USA.
⁹ Guy's and St Thomas' NHS Trust, London, UK; School of Immunology & Microbial Sciences, King's College London, London, UK.
¹⁰ Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland.
¹¹ Wellcome-Wolfson Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland.
¹² Department of Respiratory Medicine, Barts Health NHS Trust, London, UK; Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
¹³ College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Rashid Hospital, Dubai Health Authority, Dubai, United Arab Emirates.
¹⁴ Division of Clinical Respiratory Physiology Chest Department, Taipei Veterans General Hospital, Taipei City, Taiwan; COPD Assembly of the Asian Pacific Society of Respirology, Tokyo, Japan.
¹⁵ Son Espases University Hospital-IdISBa-Ciberes, Mallorca, Spain.
¹⁶ Pneumology Service, Lucus Augusti University Hospital, EOXI Lugo, Monforte, Cervo, Spain.
¹⁷ Department of Pulmonology, King Fahad Medical City, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
¹⁸ Centro de Excelencia en Asma y Alergia, Hospital Médica Sur, Ciudad de México, Mexico.
¹⁹ Microbiology Department, College of Medicine, Kuwait University, Al-Rashed Allergy Center, Ministry of Health, Kuwait.
²⁰ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
²¹ Sleep Medicine Centre, Kindai University Hospital, Osakasayama, Japan.
²² Personalized Medicine, Asthma and Allergy, Humanitas Clinical and Research Center IRCCS, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
²³ Clinical Research Centre, Smurfit Building Beaumont Hospital, Department of Respiratory Medicine, RCSI, Dublin, Ireland; Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester, UK.
²⁴ Clinical Research Centre, Smurfit Building Beaumont Hospital, Department of Respiratory Medicine, RCSI, Dublin, Ireland.
²⁵ Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester, UK; Allergy Department, 2nd Pediatric Clinic, University of Athens, Athens, Greece.
²⁶ 2nd Respiratory Medicine Department, National and Kapodistrian, University of Athens Medical School, Attikon University Hospital, Athens, Greece.
²⁷ Respiratory Research Unit, Bispebjerg University Hospital, Copenhagen, Denmark.
²⁸ CINEUMO, Respiratory Research Center, Fundación Neumológica Colombiana, Bogotá, Colombia.
²⁹ Bulagarian Alliance for Clinical and Translational Allergy, Sofia, Bulgaria.
³⁰ University Hospital "Sv. Ivan Rilski", Sofia, Bulgaria.
³¹ Allergy, Asthma & Clinical Immunology Service, Alfred Health, Melbourne, Australia; Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
³² Department of Thoracic Medicine, Concord Hospital, Sydney, Australia.
³³ Australian Severe Asthma Network, Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, Australia; Hunter Medical Research Institute, Department of Respiratory and Sleep Medicine, John Hunter Hospital, New Lambton Heights, Australia.
³⁴ Clinical Research for Allergy and Respiratory Medicine, CIDEA Foundation, Buenos Aires, Argentina; University Career of Specialists in Allergy and Clinical Immunology, Buenos Aires University School of Medicine, Buenos Aires, Argentina.
³⁵ Centre for Lung Health, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
³⁶ Medical Specialties Unit, Secretary of National Defense, Mexico City, Mexico.
³⁷ Mexican Council of Clinical Immunology and Allergy, Mexico City Office, Mexico City, Mexico; Department of Allergy and Clinical Immunology, Lic. Adolfo López Mateos Regional Hospital of the Institute of Security and Social Services for State Workers (ISSSTE), Mexico City, Mexico.
³⁸ Saw Swee Hock School of Public Health, National University of Singapore. Electronic address: wenjiach@nus.edu.sg.

PMID: 41587637
DOI: 10.1016/j.chest.2026.01.009

Free article

Interactive Pathways of Key Prognostic Factors in Severe Asthma: A Bayesian Network Comparison of Clinical Trials & Real-World Data

Chandra Prakash Yadav et al. Chest. 2026.

Free article

. 2026 Jan 24:S0012-3692(26)00125-X.

doi: 10.1016/j.chest.2026.01.009. Online ahead of print.

Authors

Affiliations

¹ Saw Swee Hock School of Public Health, National University of Singapore.
² Optimum Patient Care Global, Cambridge, UK; Observational and Pragmatic Research Institute, Singapore, Singapore; Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK.
³ Centre for Quantitative Medicine, Duke NUS Medical School, Singapore.
⁴ Medical Research Institute of New Zealand, Wellington, New Zealand.
⁵ Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
⁶ Duke-NUS Medical School, Singapore; Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore.
⁷ Division of Allergy & Clinical Immunology, Department of Medicine, National Jewish Health, Denver, CO, USA; Division of Allergy & Clinical Immunology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
⁸ NJH Cohen Family Asthma Institute, Department of Medicine, National Jewish Health, Denver, CO, USA.
⁹ Guy's and St Thomas' NHS Trust, London, UK; School of Immunology & Microbial Sciences, King's College London, London, UK.
¹⁰ Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland.
¹¹ Wellcome-Wolfson Centre for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland.
¹² Department of Respiratory Medicine, Barts Health NHS Trust, London, UK; Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
¹³ College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Rashid Hospital, Dubai Health Authority, Dubai, United Arab Emirates.
¹⁴ Division of Clinical Respiratory Physiology Chest Department, Taipei Veterans General Hospital, Taipei City, Taiwan; COPD Assembly of the Asian Pacific Society of Respirology, Tokyo, Japan.
¹⁵ Son Espases University Hospital-IdISBa-Ciberes, Mallorca, Spain.
¹⁶ Pneumology Service, Lucus Augusti University Hospital, EOXI Lugo, Monforte, Cervo, Spain.
¹⁷ Department of Pulmonology, King Fahad Medical City, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
¹⁸ Centro de Excelencia en Asma y Alergia, Hospital Médica Sur, Ciudad de México, Mexico.
¹⁹ Microbiology Department, College of Medicine, Kuwait University, Al-Rashed Allergy Center, Ministry of Health, Kuwait.
²⁰ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
²¹ Sleep Medicine Centre, Kindai University Hospital, Osakasayama, Japan.
²² Personalized Medicine, Asthma and Allergy, Humanitas Clinical and Research Center IRCCS, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
²³ Clinical Research Centre, Smurfit Building Beaumont Hospital, Department of Respiratory Medicine, RCSI, Dublin, Ireland; Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester, UK.
²⁴ Clinical Research Centre, Smurfit Building Beaumont Hospital, Department of Respiratory Medicine, RCSI, Dublin, Ireland.
²⁵ Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester, UK; Allergy Department, 2nd Pediatric Clinic, University of Athens, Athens, Greece.
²⁶ 2nd Respiratory Medicine Department, National and Kapodistrian, University of Athens Medical School, Attikon University Hospital, Athens, Greece.
²⁷ Respiratory Research Unit, Bispebjerg University Hospital, Copenhagen, Denmark.
²⁸ CINEUMO, Respiratory Research Center, Fundación Neumológica Colombiana, Bogotá, Colombia.
²⁹ Bulagarian Alliance for Clinical and Translational Allergy, Sofia, Bulgaria.
³⁰ University Hospital "Sv. Ivan Rilski", Sofia, Bulgaria.
³¹ Allergy, Asthma & Clinical Immunology Service, Alfred Health, Melbourne, Australia; Public Health and Preventive Medicine, Monash University, Melbourne, Australia.
³² Department of Thoracic Medicine, Concord Hospital, Sydney, Australia.
³³ Australian Severe Asthma Network, Priority Research Centre for Healthy Lungs, University of Newcastle, Newcastle, Australia; Hunter Medical Research Institute, Department of Respiratory and Sleep Medicine, John Hunter Hospital, New Lambton Heights, Australia.
³⁴ Clinical Research for Allergy and Respiratory Medicine, CIDEA Foundation, Buenos Aires, Argentina; University Career of Specialists in Allergy and Clinical Immunology, Buenos Aires University School of Medicine, Buenos Aires, Argentina.
³⁵ Centre for Lung Health, Vancouver General Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
³⁶ Medical Specialties Unit, Secretary of National Defense, Mexico City, Mexico.
³⁷ Mexican Council of Clinical Immunology and Allergy, Mexico City Office, Mexico City, Mexico; Department of Allergy and Clinical Immunology, Lic. Adolfo López Mateos Regional Hospital of the Institute of Security and Social Services for State Workers (ISSSTE), Mexico City, Mexico.
³⁸ Saw Swee Hock School of Public Health, National University of Singapore. Electronic address: wenjiach@nus.edu.sg.

PMID: 41587637
DOI: 10.1016/j.chest.2026.01.009

Abstract

Background: The way in which risk predictors combine and contribute to severe asthma exacerbations may differ between clinical trials and real-world settings.

Research question: How do the interactive pathways of risk predictors leading to severe asthma exacerbations compare under clinical trials versus real-world settings?

Study design: and Methods: The analysis involved 345 severe asthma patients from the placebo arms of two international randomized control trails (RCTs), compared to 6814 biologic-naïve patients from the International Severe Asthma Registry (ISAR). Seventeen key risk predictors including demographics, biomarkers, lung function, healthcare use, exacerbation history, long-term oral corticosteroid use, asthma control, and nasal polyps were covered. The outcome was the occurrence of severe asthma exacerbations over 365-day following study enrolment. Bayesian Networks (BNs), obtained from machine learning combined with expert knowledge, elucidated significant interplay processes of risk predictors that led to severe asthma exacerbations. External validation was performed in each other cohort respectively.

Results: RCTs revealed 44 significant arcs (i.e., probabilistic inter-dependency) between 17 risk factors, while ISAR showed 170. Despite this difference, the main downstream prediction pathways were consistent across both settings, with two key pathways: total serum immunoglobulin E level influenced blood eosinophils to predict future severe exacerbations, and severe exacerbation history directly predicted future severe exacerbations. In external validation, RCTs -BN generalized well to ISAR patients (AUC = 0.68) whereas ISAR-BN underperformed in RCT patients (AUC = 0.50), while ISAR-BN demonstrated better calibration.

Interpretation: The core pathways predicting severe asthma exacerbations were similar in both RCTs and real-world settings, with comparable predictive performance.

Keywords: Evidence-Based Healthcare; Machine Learning; Respiratory Diseases; Risk prediction.

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Interactive Pathways of Key Prognostic Factors in Severe Asthma: A Bayesian Network Comparison of Clinical Trials & Real-World Data

Affiliations

Interactive Pathways of Key Prognostic Factors in Severe Asthma: A Bayesian Network Comparison of Clinical Trials & Real-World Data

Authors

Affiliations

Abstract

LinkOut - more resources

Full Text Sources